2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) inhibits proliferation and invasion via senescence pathway induction in human BRAFi-resistant melanoma cells
The endogenous estradiol derivative 2-Methoxyestradiol (2-ME) has shown good and wide anticancer activity but suffers from poor oral bioavailability and extensive metabolic conjugation. However, its sulfamoylated derivative, 2-methoxyestradiol-3,17-O,O-bis-sulfamate (STX140), has superior potential...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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MDPI
2023
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| _version_ | 1797110891587567616 |
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| author | Franco, YA Oliveira de Moraes, Jr., M Carvalho, LAC Dohle, W Oliveira da Silva, R Noma, IHY Lima, K Potter, BVL Machado-Neto, JA Maria-Engler, SS |
| author_facet | Franco, YA Oliveira de Moraes, Jr., M Carvalho, LAC Dohle, W Oliveira da Silva, R Noma, IHY Lima, K Potter, BVL Machado-Neto, JA Maria-Engler, SS |
| author_sort | Franco, YA |
| collection | OXFORD |
| description | The endogenous estradiol derivative 2-Methoxyestradiol (2-ME) has shown good and wide anticancer activity but suffers from poor oral bioavailability and extensive metabolic conjugation. However, its sulfamoylated derivative, 2-methoxyestradiol-3,17-O,O-bis-sulfamate (STX140), has superior potential as a therapeutic agent, acts by disrupting microtubule polymerization, leading to cell cycle arrest and apoptosis in cancer cells and possesses much better pharmaceutical properties. This study investigated the antiproliferative and anti-invasive activities of STX140 in both SKMEL-28 naïve melanoma (SKMEL28-P) cells and resistant melanoma cells (SKMEL-28R). STX140 inhibited cell proliferation in the nanomolar range while having a less pronounced effect on human melanocytes. Additionally, STX140 induced cell cycle arrest in the G2/M phase and sub-G1, reduced migration, and clonogenic potential in monolayer models, and inhibited invasion in a 3D human skin model with melanoma cells. Furthermore, STX140 induced senescence features in melanoma and activated the senescence machinery by upregulating the expression of senescence genes and proteins related to senescence signaling. These findings suggest that STX140 may hold potential as a therapeutic agent for melanoma treatment. |
| first_indexed | 2024-03-07T08:01:04Z |
| format | Journal article |
| id | oxford-uuid:cccd4efc-1ec3-402a-ae36-ea6bfcb75bda |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:01:04Z |
| publishDate | 2023 |
| publisher | MDPI |
| record_format | dspace |
| spelling | oxford-uuid:cccd4efc-1ec3-402a-ae36-ea6bfcb75bda2023-09-20T14:03:46Z2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) inhibits proliferation and invasion via senescence pathway induction in human BRAFi-resistant melanoma cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:cccd4efc-1ec3-402a-ae36-ea6bfcb75bdaEnglishSymplectic ElementsMDPI2023Franco, YAOliveira de Moraes, Jr., MCarvalho, LACDohle, WOliveira da Silva, RNoma, IHYLima, KPotter, BVLMachado-Neto, JAMaria-Engler, SSThe endogenous estradiol derivative 2-Methoxyestradiol (2-ME) has shown good and wide anticancer activity but suffers from poor oral bioavailability and extensive metabolic conjugation. However, its sulfamoylated derivative, 2-methoxyestradiol-3,17-O,O-bis-sulfamate (STX140), has superior potential as a therapeutic agent, acts by disrupting microtubule polymerization, leading to cell cycle arrest and apoptosis in cancer cells and possesses much better pharmaceutical properties. This study investigated the antiproliferative and anti-invasive activities of STX140 in both SKMEL-28 naïve melanoma (SKMEL28-P) cells and resistant melanoma cells (SKMEL-28R). STX140 inhibited cell proliferation in the nanomolar range while having a less pronounced effect on human melanocytes. Additionally, STX140 induced cell cycle arrest in the G2/M phase and sub-G1, reduced migration, and clonogenic potential in monolayer models, and inhibited invasion in a 3D human skin model with melanoma cells. Furthermore, STX140 induced senescence features in melanoma and activated the senescence machinery by upregulating the expression of senescence genes and proteins related to senescence signaling. These findings suggest that STX140 may hold potential as a therapeutic agent for melanoma treatment. |
| spellingShingle | Franco, YA Oliveira de Moraes, Jr., M Carvalho, LAC Dohle, W Oliveira da Silva, R Noma, IHY Lima, K Potter, BVL Machado-Neto, JA Maria-Engler, SS 2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) inhibits proliferation and invasion via senescence pathway induction in human BRAFi-resistant melanoma cells |
| title | 2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) inhibits proliferation and invasion via senescence pathway induction in human BRAFi-resistant melanoma cells |
| title_full | 2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) inhibits proliferation and invasion via senescence pathway induction in human BRAFi-resistant melanoma cells |
| title_fullStr | 2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) inhibits proliferation and invasion via senescence pathway induction in human BRAFi-resistant melanoma cells |
| title_full_unstemmed | 2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) inhibits proliferation and invasion via senescence pathway induction in human BRAFi-resistant melanoma cells |
| title_short | 2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) inhibits proliferation and invasion via senescence pathway induction in human BRAFi-resistant melanoma cells |
| title_sort | 2 methoxyestradiol 3 17 o o bis sulfamate stx140 inhibits proliferation and invasion via senescence pathway induction in human brafi resistant melanoma cells |
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